KR20070037436A - Heat sterilization of glucocorticosteroids - Google Patents

Abstract

The present invention relates to a method for sterilizing an unstable glucocorticosteroid, which method comprises heat-treating the unstable glucocorticosteroid in suspension form by moist heat for a time effective for sterilization. The methods and compositions of the present invention are useful as therapeutic tools for preventing, recovering and / or reducing allergic and / or inflammatory symptoms in mammalian patients. The present invention also provides methods and compositions that control the symptoms to be treated with minimal side effects and that can be fine tuned to suit the conditions to be treated.

Heat sterilization of glucocorticosteroids, aqueous suspension of glucocorticosteroids, budesonide, beclomethasone dipropionate, autoclaving

Description

Heat sterilization of glucocorticoids {HEAT STERILIZATION OF GLUCOCORTICOSTEROIDS}

The present invention relates to methods of heat sterilization in the form of suspensions of unstable glucocorticoids, sterile pharmaceutical compositions, and methods for treating allergic and / or inflammatory symptoms using such pharmaceutical compositions.

Sterile drug products offer a number of benefits both medically and economically. It is evident that sterile pharmaceuticals are needed in the medicinal field in that the use of non-sterile agents may pose an unnecessary risk of secondary infection from contaminating microorganisms that are at least resistant to the drugs of the formulation. Moreover, even if the contaminants are harmless, the growth of microorganisms in itself leads to the loss of active pharmaceuticals, with the formation of toxic by-products of toxic by-products. Economically, the shelf life of contaminated pharmaceuticals is short, and this short shelf life requires increased production costs to replace products more frequently.

The preparation of sterile products for use in a patient is needed for the method. However, problems arise in many sterilization processes, in which undesirable changes in the drug profile often occur. The range of such changes in drug profile may include loss of activity, increased degradation of the resulting product, or alteration in the chemical or physical properties of the sterilized compound. These problems arise especially when sterilizing glucocorticoids.

Sterilizing the material relies on the injection of sufficient energy that is fatal to all possible microbial contamination. Numerous methods containing heating, radiation and chemicals have been proposed to sterilize glucocorticoids. However, to date these methods have often lost activity or excessively produced degradants on sterile glucocorticoids. In addition, for glucocorticoid suspension formulations that are suitable for metered dose inhalation, the sterilization procedures commonly used often result in unacceptable changes in drug particle size.

Chemical sterilization is mostly based on exposure to toxic compounds (eg ethylene oxide). However, it has been found that ethylene oxide leaves a residual amount of ethylene oxide in drug preparation when sterilizing glucocorticoids. Ethylene oxide is toxic and residual levels exceed the pharmaceutically acceptable limits established by most regulatory actions.

Irradiation based sterilization is known and recommended for glucocorticoids (see Illum and Moeller in Arch. Pharm. Chemi. Sci., Ed. 2, 1974, pp. 167-174). However, significant degradation has been reported when irradiation is used to sterilize preparticulated glucocorticoids.

WO 02/41925 of Breath Limited describes a rapid method similar to pasteurization with respect to composition sterilization. Such methods include pumping of the composition to be sterilized through stainless steel pipes and rapidly increasing the temperature of the composition to about 130-145 ° C. for about 2-20 seconds, followed by a brief While cooling rapidly.

O'Neil, US Pat. No. 3,962,430, describes a method for producing a sterile isotonic solution of a medicament. This method involves adding the agent to a saturated solution of sodium chloride dissolved in water at 100 ° C. The drug / saturated sodium chloride solution was then heated to 100-130 ° C. This method, based on the theory known that sodium chloride ions fix free water and thereby prevent hydrolytic degradation, is not suitable for suspensions of fine particles of glucocorticoids to be inhaled, This is because it produces undesirable changes in particle size. This process can also form crosslinks between drug particles that produce large aggregates that do not degrade upon administration.

US Pat. No. 6,464,958 to Bernini et al. Discloses that heat sterilization of suspension formulations for many drugs produces undesirable changes, for example in drug profiles containing aggregation of drug particles. Some undesirable changes are modifiable. For example, aggregates formed during heat sterilization may be re-treated to break up into smaller size particles suitable for nasal administration. However, in the case of beclomethasone dipropionate, some undesirable changes cannot be corrected. For example, Bernini, with an increase in degradation products (about 10-11%) in beclomethasone suspensions sterilized by a wet steam process similar to that reported in US Pat. No. 3,962,430, supra. It has been reported that a significant reduction (about 8-9%) of active ingredient content occurs.

US Pat. No. 6,392,036 to Karlsson et al. Describes a method that can be dry heat sterilized to powdered saccharide corticosteroids for use in drug formulations.

There is a need for a method of sterilizing a glucocorticoid pharmaceutical composition of a suspension. Sterilization should not cause loss of drug activity, minimize the production of degradation products and at the same time not cause pharmaceutically unacceptable changes in drug particle size. Ideally, in the case of sterile pharmaceutical products, the final step in the preparation of this product should be a sterilization process, thereby minimizing the possibility of contamination during the preparation process.

Summary of the Invention

The present invention relates to a method for sterilizing a glucocorticosteroid, comprising heating an aqueous suspension of a glucocorticosteroid, wherein the glucocorticosteroid has a sufficiently low solubility in water and is a glucocorticosteroid during heating At least 50% of the is used in a sufficient amount in the form of a suspension.

Aspects of the present invention describe a method for sterilizing an unstable glucocorticoid, comprising exposing a suspension of the unstable glucocorticosteroid during moist heat during a sterilizing-effective time.

Another aspect of the invention describes a composition comprising a sterile unstable saccharide corticosteroid suspension prepared according to the methods described herein.

1 is a graph showing the budesonide content in the concentrated budesonide samples after sterilization in the sterilization conditions described in the drawings. The horizontal axis represents the concentrate tested, while the vertical axis represents the percentage of budesonide present.

FIG. 2 graphically depicts the total budesonide impurities (including both measured and unknown samples) in concentrated budesonide samples after sterilization under the sterilization conditions described in the figures. The horizontal axis represents the concentrate tested, while the vertical axis represents the percentage of impurities after heating.

FIG. 3 graphically shows budesonide digestion in diluted samples after sterilization at the sterilization conditions described in the figures. FIG. The horizontal axis represents the tested budesonide concentration (mg / ml), while the vertical axis represents the impurity concentration present depending on the heating conditions.

Figure 4 graphically shows the maximum particle size distribution of budesonide in diluted samples after sterilization at the sterilization conditions described in the figures. The horizontal axis shows the tested budesonide concentration (mg / ml), while the vertical axis shows the upper threshold for particle size with heating of the suspension formulation.

The present invention provides a method for sterilizing a glucocorticosteroid, comprising heating an aqueous suspension of glucocorticosteroids, wherein the glucocorticosteroid has a sufficiently low solubility in water and at least 50% is used in a sufficient amount in the form of a suspension. The methods and compositions of the present invention are useful as therapeutic means to prevent, recover and / or reduce signs of allergic and / or inflammatory symptoms in a mammalian patient. The invention also provides methods and compositions that can be prepared and fine tuned to the conditions to be treated while minimizing side effects.

Glucocorticoids are "unstable" glucocorticosteroids, meaning chemically or physically unstable states caused by external forces applied to chemical compounds or compositions. By way of non-limiting example, acid instability or temperature instability means that undesired degradation (eg, pharmaceutical or physicochemical degradation) occurs when the chemical compound is exposed to each particular acid or temperature condition.

As used herein, "glucocorticoid" or "glucocorticoid" means all groups of steroid hormones, including cortisone, including derivatives, synthetic analogs and prodrugs thereof, produced by the adrenal cortex. These compounds are associated with carbohydrate, protein and fat metabolism. In addition, glucocorticoids exhibit anti-inflammatory properties.

The glucocorticoid used in the present invention is preferably an anti-inflammatory glucocorticoid. Non-limiting examples of glucocorticoids that can be used in the present invention include beclomethasone, budesonide, ciclesonide, cortibazole, deplazacoat, flumethasone, flunisolide, flocinolone , Fluticasone, mometasone, rofleponide, tipredane and triamcinolone. Preferably, budesonide, beclomethasone (eg dipropionate), ciclesonide, fluticasone, mometasone and triamcinolone are used. Most preferably, budesonide and beclomethasone are used.

Unless defined otherwise, technical and scientific terms used herein have the meanings that are commonly understood by one of ordinary skill in the art to which this invention pertains. Various methodologies and materials known to those skilled in the art are described in the references cited herein. Standard references describing general principles of pharmacology are Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10 ^th Ed., McGraw Hill Companies Inc, New York (2001). All suitable materials and / or methods known to those skilled in the art can be used to carry out the present invention.

The patents and scientific documents described herein establish knowledge of those skilled in the art and are designated herein by reference, each of which is specific and individually cited herein, such patents and scientific documents are incorporated herein by reference. It is. All contradictions between all references described herein and the particular techniques herein can be resolved by the following. Likewise, all contradictions between the definitions of terms or phrases understood in the art and the definitions of terms or phrases specifically described in the detailed description of the invention may be resolved by the following.

Unless defined otherwise, the singular forms, including the singular forms “a”, “an” and “the”, also in the description of the invention and in the appended claims also include the plurals of the above terms. Also, unless specifically defined otherwise, the term "or" is used in the "inclusive" sense of "and / or" but not in the "inclusive" sense of "or / or".

As used in the description of the invention, the terms "comprise" and "comprising" in the transitional phrases and features of the claims are to be construed as having an open meaning. That is, the term may be interpreted synonymously with phrases such as "having at least" or "including at least". When used in the context of a method, the term "comprising" means that the method includes at least the steps described, but may also include additional steps. When used in the context of a compound or composition, the term "comprising" means that the compound and composition include at least the property or component described, but may also include additional properties or components.

Specific embodiments of the invention are described in detail below. While the invention will be described in connection with these specific embodiments, it will be understood that it is not intended to limit the invention to those specific embodiments. In contrast, alternatives, modifications, and equivalents of the present invention are considered to be within the spirit and scope of the present invention as set forth in the appended claims. In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. The present invention may be practiced without some or all of these specific substrates. In other instances, well known methods have not been described in detail in order not to unnecessarily obscure the present invention.

Aspects of the present invention provide methods for heat sterilization of labile glucocorticoids. The method of this aspect includes exposing a suspension of glucocorticoids that are unstable during sterilization-effect time to moist heat. The present application has found that, due to the limitations of the sterilization parameters and the properties of the glucocorticoid, the formation of unwanted by-products as well as the undesirable increase in the size of the particles of the glucocorticoid can be avoided. Carbohydrate corticosteroids should have a sufficiently low solubility in the suspension solvent, and only a portion of the glucocorticosteroid is used at a sufficiently high concentration to dissolve in the suspension solvent. In this way, recrystallization of the glucocorticoids occurs during cooling, which allows the decomposition of the glucocorticosteroids to avoid minimizing by-products and undesirably increasing particle size.

In order for at least 50% of the glucocorticoid to be suspended in a solvent, a balance is required between the solubility of the glucocorticosteroid and the amount of glucocorticosteroid used per unit of solvent. For example, for budesonide, the solubility in water at sterilization temperature as used herein is about 7 mg / ml. Therefore, 15 mg of budesonide used per 1 mg of water provides 53% of budesonide as a suspension. While this value may be at least 70% or at least 80%, it is preferred that at least 60% of the glucocorticoids be suspended in a solvent.

In this way, a sufficient amount of sodium chloride to form a saturated solution of sodium chloride as described in US Pat. No. 3,962,430 (see above) to control the solubility of the glucocorticoid in water. There is no need to mix them. The method of the present invention is preferably carried out with a control agent that is substantially insoluble, and the control factor does not have a significant effect on the solubility of the glucocorticoid in water.

The maximum amount of glucocorticoid is not important if the suspension is still formed. Excess saccharide corticosteroids, however, form an intractable paste. In an embodiment, the preferred maximum amount of budesonide is about 150 mg / ml.

As shown in the examples below, significant increases in impurities can be avoided by heating the suspension under these conditions. For example, in the case of budesonide, the concentration of decomposition product 1,2-dihydro budesonide is preferably lower than 0.2% by weight based on the amount of budesonide present in the suspension. Degradation products can be measured by standard techniques, such as HPLC, as described in the Examples below.

In an embodiment, the labile glucocorticoid is budesonide and the heating step is carried out by autoclaving at about 121 ° C. for about 20 to about 30 minutes or at about 110 ° C. for about 115 to about 150 minutes. In another embodiment, the labile glucocorticosteroid is beclomethasone dipropionate and the heating step is at high pressure at about 121 ° C. for about 20 to about 30 minutes or at about 110 ° C. for about 115 to about 150 minutes. Carry out steam sterilization. In another embodiment, the labile glucocorticoid is present at a concentration of about 15 mg / ml to about 150 mg / ml.

As used herein, “humid heat” means that the heat is transferred to the water by applying heat to the composition, which affects the sterilization of the composition to be treated, causing partial vaporization of water when heated above 100 ° C. to form vapors. do. Wet heat is the heating of compounds and compositions at about 101 ° C. to about 145 ° C., preferably at about 110 ° C. to about 138 ° C., and most preferably at about 121 ° C. to about 138 ° C. Preferably, the heating is carried out by autoclaving.

"Sterile" means that the product or composition meets the sterile criteria set forth in US Pharmacopoeia 27 / NF22, 2004 or a copy thereof within another jurisdiction, which is a therapeutically acceptable glucocorticoid and / or pharmaceutical Formulations are provided.

The term "sterilizing-effective time" means the minimum time required to be effective for sterilization under specified conditions. The sterilization-effect time is preferably about 2 minutes to about 180 minutes.

In another embodiment, the glucocorticoid suspension also includes pharmaceutically acceptable surfactants that are well known in the art, such as polysorbate, which is polysorbate 80. If surfactant is present, the surfactant is preferably present at a concentration of about 0.2 mg / ml to about 60 mg / ml.

Other embodiments of this aspect of the invention also include the step of diluting the suspension to a pharmaceutically suitable concentration with a pharmaceutically acceptable excipient, diluent, and the like.

The term "about" means the approximate range, approximate value or surrounding value of a given value. When the term “about” is used in connection with a numerical range, the range is modified by extending the upper and lower limits of the numerical values set forth. In general, the term "about" modifies the upper and lower limits of the values determined by a dispersion of 20%.

As used herein, the description of a numerical range for a variable is considered to mean that the invention can be performed with a variable corresponding to all numerical values within the scope. Thus, for essentially non-continuous variables, these variables correspond to all integers in the numerical range, including the end-point of the range. Similarly, for essentially continuous variables, these variables correspond to all real numbers in the numerical range, including the end point of the range. For example, a variable described as having a value between 0 and 2 is 0, 1 or 2 for essentially non-continuous variables, 0.0, 0.1, 0.01, 0.001 or All other mistakes.

The methods and compositions of the present invention are for use in any mammal that can benefit from the methods of the present invention. Although the present invention is not intended to be limited as follows and may be used for veterinary purposes, an important example of such mammals is humans. Thus, "mammal" or "mammal in need" of the present invention includes humans as well as non-human mammals, particularly livestock animals including but not limited to cats, dogs, and horses.

Another aspect of the present invention provides a suspension composition of sterile labile saccharide corticosteroids prepared according to the method of the first aspect of the invention described above. In some embodiments, the composition is a pharmaceutical composition for treating or alleviating signs of allergic and / or inflammatory symptoms in a mammalian patient. In such embodiments, the composition contains a sterile, labile glucocorticoid, dissolved in a therapeutically effective amount of a pharmaceutically acceptable carrier. In some embodiments, the glucocorticoid is budesonide, and in another embodiment beclomethasone is used.

The term “therapeutically effective amount” means to provide treatment in an effective dosage to obtain the desired therapeutic result. In addition, those skilled in the art can reduce the therapeutically effective amount of a compound of the invention by making minor adjustments and / or administering one or more compounds of the invention, or administering a compound of the invention in combination with other compounds. Or can be increased. The present invention therefore provides a method of adjusting administration / treatment for a particular requirement of a given mammal.

Another embodiment relates to a composition in which there is an unstable glucocorticosteroid in combination with a second active ingredient. In some embodiments, the second active ingredient is selected from albuterol, ifpratropium bromide and chromoline.

In another embodiment of this aspect, the compositions of the present invention may be administered orally, inhaled, rectally, eyes (including intravitreal or intracameral), nose, topical (oral and sublingual), vaginal or Suitably formulated for parenteral administration (including subcutaneous, intramuscular, intravenous, intradermal and intratracheal). The composition is preferably formulated for inhalation, in which case Dv100 is less than 20 μm, Dv90 is less than 10 μm and Dv50 is less than 5 μm in terms of the particle size of the glucocorticosteroid, where Dvn is It represents the volume diameter at the nth percentile. Volume diameter is a term known in the art and refers to the diameter of a sphere if any substance has a volume of particles. Particle sizes can be measured by standard techniques such as laser diffraction as described in the Examples described herein below. Such particle size can be obtained using heat sterilization conditions as described herein.

Formulations of the compositions of the present invention may conveniently be presented in unit pharmaceutical formulations and may be prepared using conventional pharmaceutical techniques. Such techniques include the step of combining a compound of the invention and a pharmaceutically acceptable carrier such as a diluent or prosthetic. Generally, the composition is prepared by equally and intimately combining the active ingredient with a liquid, a finely divided solid carrier or both, and then molding the product if necessary.

Sterile, unstable saccharide corticosteroids prepared according to the invention are optionally formulated into pharmaceutically acceptable excipients with well known pharmaceutically acceptable carriers including diluents and prosthetics (Remington's Pharmaceutical Sciences, 18 ^th Ed , Gennaro, Mack Publishing Co., Easton, PA 1990 and Remington: The Science and Practice of Pharmacy, Lippincott, Williams & Wilkins, 1995). The type of pharmaceutically acceptable carrier / excipient used to prepare the composition in this aspect of the invention will vary depending on the method of administering the composition to the mammal. In general, pharmaceutically acceptable carriers are physiologically inert and non-toxic. Formulations of the compositions according to the invention may contain one or more types of pharmacologically active ingredients useful in the treatment of the signs / symptoms to be treated.

In another aspect, the present invention provides a method of using the composition of the present invention to treat or alleviate allergic and / or inflammatory symptoms in a mammalian patient. Such methods include administering a therapeutically effective amount of a labile glucocorticoid in a pharmaceutically acceptable excipient. In various embodiments of this aspect, a therapeutically effective amount of a glucocorticoid is administered orally, inhaled, rectally, eye, vaginally or parenterally in combination with only a glucocorticoid or a second effective ingredient. In some embodiments, the glucocorticoid is budesonide, while in another embodiment the glucocorticosteroid is beclomethasone.

The present invention further provides sterile glucocorticoids, preferably anti-inflammatory glucocorticosteroids, for use in treating allergic and / or inflammatory symptoms. The allergic and / or inflammatory symptoms to be treated do not need to be limited to one anatomical site, such as the nose or the lung, and the compositions of the present invention are formulated for proper administration to the site of treatment. Allergic and / or inflammatory symptoms include, but are not limited to, contact dermatitis, asthma, rhinitis or chronic obstructive pulmonary disease. The present invention also provides the use of sterile glucocorticoids in the manufacture of a medicament (preferably sterile medicament) for the treatment of allergic and / or inflammatory symptoms.

The following examples are intended to further illustrate certain embodiments of the present invention, but are not intended to limit the present invention. Those skilled in the art can recognize or identify numerous equivalents to the particular materials and methods of manufacture described herein using only general experimentation.

Example  One

Budesonide   Heat sterilization

The high-density mixer was homogenized and placed in a sealed container to suspend the solid material to prepare a concentrated budesonide sample which was heated at the time and temperature shown in Table 1. The sample was heated at the indicated time and temperature.

HPLC analysis was performed using a UV / vis detector to sequentially analyze heated and concentrated samples to determine the content of budesonide and the impurity levels (both measured and unknown). It is shown in Table 2-5.

Concentrated budesonide samples were also analyzed for particle size using laser diffraction and this dispersion is shown in Table 6. In Figures 1 and 2 the budesonide content and total impurities of the heat stressed concentrate are shown graphically, respectively.

Sterilization was confirmed using a spore strip bioindicator treated simultaneously with the sample concentrate.

Heat-induced digestion (0.004, 0 and 0.003% different from untreated control, respectively) at the lowest amount when treated higher concentrations of concentrate (concentrates B, C and D) (121 ° C. for 20 minutes) The results are shown. Heat induced decomposition was greatest in Concentrate A (37.5 mg / ml) during heating. Comparable results were also observed in the particle size analysis shown in Table 6.

Example  2

Budesonide   Heat Sterilization-Study 2

The apparent concentration-dependent decrease in degradation product formation observed in Example 1 led to the following study to determine the lowest budesonide concentration limit that could be sterilized while maintaining acceptable degradation and particle size. Samples were prepared according to the preparation method of Example 1 except that the heating and time of exposure were limited to 121 ° C. for 30 minutes.

Table 7 lists the budesonide concentrations of the serial dilutions prepared. The heated and diluted samples were analyzed to determine the budesonide content and impurity levels (both measured and unknown) and these results are shown in Table 8 together with the particle size distribution shown in Table 9. 3 and 4 show the budesonide content and total impurities of the diluted sample heat-modified, respectively. Sterilization was confirmed using a bioindicator heated simultaneously with the sample concentrate.

The data from these studies confirmed the above observations that the lower the concentration of corticosteroids that could be heat sterilized, the greater the production of associated degradation products. It can be seen that the lowest concentration to produce an acceptable heat sterilized product based on the total digest produced and the resulting particle size is about 15 mg / ml (see FIGS. 3 and 4).

Example  3

Beclomethasone Dipropionate   Heat sterilization

The preparation method of Example 1 was used to prepare beclomethasone concentrates and dilutions as shown in Table 10. It was also measured as described above to determine impurity levels and particle size. The results (data not shown) show no significant change in the content of beclomethasone or a significant increase in impurities upon heating in the autoclave. In addition, autoclaving showed no significant change in particle size dispersion.

Equivalent

The claimed invention is described in detail in conjunction with specific embodiments thereof, and various changes and modifications that can be made by the claimed invention without departing from the spirit and scope of the art will be apparent to those skilled in the art. Therefore, one of ordinary skill in the art can recognize or identify numerous equivalents to the particular materials and methods of manufacture described herein using only general experimentation. Such equivalents are considered to be within the scope of this invention and are covered by the following claims.

Claims (17)

A method of sterilizing an unstable glucocorticosteroid, comprising exposing a suspension of the unstable glucocorticoid to moist heat for a sterilizing-effective time. A method of sterilizing a glucocorticoid, comprising heating an aqueous suspension of a glucocorticosteroid, wherein the glucocorticosteroid has a sufficiently low solubility in water and at least 50% of the glucocorticosteroid is suspended during heating. A method of sterilizing glucocorticoids used in a sufficient amount in form. The method of claim 2, wherein at least 60% of the glucocorticoids is in suspension form during heating. The method of any one of the preceding claims, characterized in that the heating is carried out at a temperature of about 101 ° C to about 145 ° C. The method according to any one of the preceding claims, characterized in that the heating is carried out by autoclaving. The method of claim 1, wherein the heating is performed from about 2 minutes to about 180 minutes. The method of any one of the preceding claims wherein the suspension further comprises a surfactant. 8. The method of claim 7, wherein the surfactant is present at a concentration of about 0.75 mg / ml to about 60 mg / ml. The method of any one of the preceding claims, wherein the glucocorticoid is budesonide or beclomethasone dipropionate. The method of claim 9, wherein the glucocorticoid is budesonide and heated at 121 ° C. for about 20-30 minutes or at 110 ° C. for about 120 minutes. 10. The method of claim 9, wherein the glucocorticoid is beclomethasone dipropionate and heated at 121 ° C. for about 20-30 minutes or at 110 ° C. for about 120 minutes. The method of claim 1, wherein the glucocorticoid is present at a concentration of about 15 mg / ml to about 150 mg / ml. Sterilizing budesonide, comprising heating the aqueous suspension of budesonide at a concentration of about 15 mg / ml to about 150 mg / ml at a temperature of about 101 ° C. to about 145 ° C. for about 2 minutes to about 180 minutes. How to let. The method of any one of the preceding claims, further comprising diluting the suspension to a pharmaceutically suitable concentration. A composition obtainable by the method of any one of the preceding claims. A sterile aqueous suspension comprising a glucocorticoid obtained by the method of any one of claims 1 to 14, wherein the Dv100 is less than 20 μm in particle size of the glucocorticosteroid, A sterile aqueous suspension comprising a glucocorticoid, wherein Dv90 is less than 10 μm and Dv50 is less than 5 μm. A sterile aqueous budesonide suspension obtained by the method of any one of claims 1 to 14, wherein the suspension is less than 0.2% by weight based on the amount of budesonide. A sterilized budesonide aqueous suspension comprising, 2-dihydro budesonide.

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